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Stratified based on age and estrogen status from 3 to 6 mcg/kg/day

Somatropin

Dosage based on age and estrogen status ranging from 3 to 6 mcg/kg/day

Placebo

Anne Klibanski, M.D

The purpose of the study is to evaluate the effects of growth hormone replacement on women with growth hormone deficiency. Growth hormone deficiency means the body no longer produces growth hormone due to a tumor or some kind of disease of the brain in an area called the pituitary/hypothalamic region. This is the area of the brain where growth hormone is normally produced. We, the researchers at Massachusetts General Hospital, will establish the effects of growth hormone replacement on cardiovascular parameters (laboratory tests, the flexibility of the arteries, changes in heart rate) in women with growth hormone deficiency. Our goal is to see if this therapy:

* has effects on women's cardiovascular risk markers (special blood tests which indicate how healthy the heart and arteries are)
* has effects on women's types and levels of various substances circulating in their blood
* in women affects the stiffness of their arteries and heart rate variability in parallel with changes in cardiovascular risk markers
* has different effects depending on whether women are pre or post menopausal.

Participation in this study is expected to last approximately 12 months.

The aim of the study is to evaluate the gender specific effects of physiologic Growth Hormone (GH) replacement in women with GH deficiency on the basis of pituitary/hypothalamic region tumors, radiation, or surgery on cardiovascular risk markers and arterial distensibility. Cardiovascular mortality in growth hormone (GH) deficient adults has been shown to be increased in a number of retrospective studies. Increased arterial intima-media thickness, increased prevalence of atherosclerotic plaques and endothelial dysfunction have been reported in growth hormone deficient adults both in childhood and adulthood onset forms.

The growth hormone deficiency (GHD) syndrome is associated with a cluster of cardiovascular-risk factors such as central adiposity, increased visceral fat, insulin resistance, dyslipoproteinemia and decreased plasma fibrinolytic activity. GH administration has effects on a number of these factors, but it is unknown which mechanisms are implicated in GH action on the process of atherosclerosis. In addition to alterations in atherosclerotic markers, abnormalities in cardiac function and structure have been reported among patients with GHD possibly contributing to the increased cardiovascular mortality. In addition, GHD is associated with cardiac autonomic dysfunction that may also contribute to cardiovascular mortality and improves with GH replacement therapy.

The vast majority of studies have focused primarily on men and the gender-specific effects of GH replacement on cardiovascular risk factors remain unknown. In addition to being of interest in terms of understanding the physiologic effects of GH therapy, there are important therapeutic implications regarding data in women. Cardiovascular disease is the leading cause of mortality in women. Effects of GH replacement on bone density may be less pronounced in women and because specific GH effects on cardiovascular risk factors in women are unknown, many adult women with GHD are untreated.

Long-term GH treatment decreases total body fat including visceral fat. Decreases in central fat as assessed by waist to hip ratio have been reported in some studies, but not in others. Administration of GH causes insulin resistance acutely but long-term therapy may restore glucose sensitivity. GH treatment increases lipoprotein (a) (Lp (a)) levels but its effects on other lipoproteins are still controversial. Some studies have reported decreases in LDL cholesterol with or without increases in HDL cholesterol with GH administration, while others have not. Twelve months of GH replacement improves left ventricular mass and cardiac performance in young adults with GHD. Key factors likely involved in the discrepant findings include heterogeneity of patients studied in terms of age of onset of the GH deficiency (childhood versus adulthood), gender, severity of GHD and methodologic issues such as dose and duration of GH administration. In addition, many of the studies have no control period.

Inflammation plays a central role in the pathophysiology of atherosclerosis. Each atherosclerotic lesion represents a different stage of a chronic inflammatory process in the arterial wall and different markers along the inflammatory cascade have been reported to predict cardiovascular risk \[34\]. Among those, high-sensitivity testing for C-reactive protein (CRP) is one of the best validated. Several prospective studies support a strong link between levels of CRP and future risk of coronary events. CRP adds considerable value to the total and HDL cholesterol measurement in the prediction of cardiovascular risk. Other distal indicators of inflammation such as serum-amyloid polypeptide A (SAA) likewise predict coronary risk. These distal markers reflect the consequences of elevated proinflammatory cytokines like interleukin-6 (IL-6). GH is known to have important immunomodulatory effects. We therefore hypothesized that the effects of GH on the process of atherosclerosis might be mediated through the cytokine-inflammatory pathway. We have recently investigated the effects of physiologic GH replacement in cardiovascular risk markers in men with GHD. In this study we found that CRP and IL-6 levels decreased in GH treated men compared to controls despite no significant change in serum lipid levels. We also recently have investigated levels of inflammatory markers in women with hypopituitarism compared with healthy controls. We found that women with hypopituitarism have increased levels of IL-6 and CRP suggesting that chronic inflammation may be involved in the pathogenesis of atherosclerosis in this population. It will be critical to determine whether physiologic GH replacement has beneficial effects in women, and whether these effects are influenced by estrogen.

We will investigate the effect of long-term physiologic GH administration on IL-6, CRP, SAA as well as other classic cardiovascular risk factors in women with GHD in a randomized, placebo-controlled study. In addition, we will evaluate structural/function correlates in women by measuring arterial wall distensibility and heart rate variability in parallel with cardiovascular risk markers.

We will establish the gender-specific effects of physiologic GH replacement on cardiovascular risk in women with GHD by investigating whether this therapy:

1. has gender-specific effects on cardiovascular risk markers
2. has gender-specific effects on lipid profiles
3. alters heart rate variability and arterial distensibility in parallel with changes in cardiovascular risk markers
4. has different effects depending upon gonadal status

Growth Hormone Administration and Its Effects on Cardiovascular Risk Factors in Growth Hormone Deficient Women

Gender-Specific Effects of Physiologic GH Administration on Cardiovascular Risk Factors in Women With Growth Hormone Deficiency

Massachusetts General Hospital

Anne Klibanski, MD

Symptoms and General Pathology

Heart and Blood Diseases

Nutritional and Metabolic Diseases

Syndrome

Atherosclerosis

Metabolic Syndrome

Insulin Resistance

Arteriosclerosis

Arterial Occlusive Diseases

Vascular Diseases

Endocrine Gland Neoplasms

Hypothalamic Neoplasms

Supratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Hypoglycemic Agents

Insulin

Insulin, Globin Zinc

Hormone Antagonists

Recombinant Growth Hormone, Genotropin (Pfizer)

Annamaria AL Colao, Prof.

Adult patients with hypopituitarism under adequate conventional hormone replacement therapy have reduced life expectancy due to excess vascular events (1-4). Deficiency in GH secretion (GHD) is likely to play a major role in determining the excess mortality, since it is associated with lipid abnormalities, visceral adiposity, glucose intolerance, insulin resistance, hypertension, cardiac abnormalities and increased intima-media thickness (IMT) at major arteries (5).

Beneficial effects of growth hormone (GH) replacement on cardiovascular risk factors have been demonstrated in several studies of hypopituitary GHD patients (5). GH replacement improves body composition and lipid profile (5): it is accepted that management of dyslipidaemia is crucial in primary and secondary prevention of cardiovascular disease and part of the excess vascular risk associated with hypopituitarism is likely to be due to dyslipidaemia (6). A meta-analysis of blinded, randomized, placebo-controlled trials with low doses and long-duration GH treatment showed that GH replacement has beneficial effects on cardiovascular risk by improving lean and fat body mass, total and LDL cholesterol levels, and diastolic blood pressure (7). Besides, GH replacement also induces improvement in cardiovascular markers (8), and cardiac performance (9). In small cohorts of GHD adults, beneficial effects of GH replacement for 6-24 mos have also been reported on surrogate parameters of atherosclerosis, such as intima-media thickness (IMT) at major arteries (10-13), while 6 months of GH deprivation is associated with an impairment of the cardiovascular risk profile (12). In a consistent series of men and women with hypopituitarism we reported, however, that two years of GH replacement is not adequate to normalize IMT levels at common carotid arteries (13).

To give further insights on the likelihood of reversal of early atherosclerosis in severe GHD patients after prolonged GH replacement, we designed this 5-yr prospective, controlled study. Only men aged ≤50 yrs and with severe GHD were enrolled to avoid gender and aging interference (13). Main outcome measure was IMT at common carotid arteries; secondary measure was prevalence of insulin-resistance syndrome according with the American College of Endocrinology (14).

This is an observational,5-yr prospective, controlled study. At study entry, all subjects underwent serum assay of IGF-I, systolic and diastolic blood pressure (SBP, DBP) measurement, total-, and HDL-cholesterol, triglycerides, glucose, and insulin level after an overnight fasting, and common carotid arteries ultrasonography. The oral glucose load (oGTT) was performed by measuring blood glucose every 30 minutes for 2 hours after the oral administration of 75 g of glucose diluted in 250 ml of saline solution. The conversion factors (mg/dl to mmol/l) for lipids and glucose were as follows: cholesterol 0.02586, triglycerides 0.01129, and glucose 0.05551. According with previous studies (13,19-21) blood pressure was measured at the right arm, with the subjects in relaxed sitting position. The average of six measurements (three taken by each of two examiners, in the same day, between 8.00-9.00 in the morning) with a mercury sphygmomanometer was used in all analysis.

In the patients, all parameters and carotid ultrasonography were re-evaluated after 12, 24, 36, 48 and 60 months while in controls they were re-evaluated after 60 months.

At study entry and at study end, in all of the patients and controls the prevalence of insulin-resistance syndrome (IRS) was evaluated according with the American College of Endocrinology (14) based on the presence of at least two criteria of the following: triglycerides levels ≥1.7 mmol/liter, HDL-cholesterol levels ≤1.0 mmol/liter, blood pressure above 130/85 mmHg, fasting glucose between 6.1 and 7 mmol/liter or 2 hr after oGTT between 7.7 and 11.1 mmol/liter.

Effect of 5 Years of GH Replacement on Atherosclerosis

Phase 4 Study of Recombinant GH on Intima-Media Thickness at Common Carotids and on Cardiovascular Risk Factors in Hypopituitary Patients

Federico II University

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Growth Hormone Administration and Its Effects on Cardiovascular Risk Factors in Growth Hormone Deficient Women	NCT00136032	Growth Hormone ...	Somatropin Placebo	18 Years - 65 Years	Massachusetts General Hospital
Effect of 5 Years of GH Replacement on Atherosclerosis	NCT00462475	Hypopituitarism Pituitary Tumor... Growth Hormone ...	Recombinant Gro...	18 Years - 50 Years	Federico II University

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